The objectives of this project are to develop an efficient synthesis of the recently discovered molecule lactonamycin and to prepare analogs of it that optimize its biological activity. Lactonamycin's hexacyclic structure is unlike that of any other compound. It exhibits potent activity against bacteria resistant to existing antibiotics including methicillin-resistant (MSRA) and vancomycin-resistant (VRE) strains. Lactonamycin also possesses significant anticancer activity. In the course of our work we intend to explore new general strategies for achieving stereo-, regio-, and enantioselective transformations. The specific aims are: To develop a short and efficient synthesis of lactonamycin. To use that effort as an opportunity to explore new general strategies for accomplishing stereo-, regio-, and enantiocontrolled synthetic transformations including (i) extending the role of intramolecular hydrogen bonding and/or borate complexation in Diels-Alder reactions, (ii) developing a dynamic thermodynamic (as opposed to kinetic) resolution, and (iii) examining new ligands for controlling intramolecular delivery of OsO4 under circumstances where Sharpless-type asymmetric dihydroxylation is expected to fail. To employ the synthetic route to prepare analogs of lactonamycin with the aim of (i) making available water-soluble derivatives of lactonamycin, (ii) separating and optimizing the antibiotic and antitumor activities, (iii) identifying the pharmacophores, and (iv) beginning SAR studies. To test, in collaboration with Pfizer Inc., analogs and synthetic intermediates for antibiotic, anticancer and other biological activities.